CD89 Triggers APRIL Activation in Pediatric IgA Nephropathy
Bibliographic record
Abstract
Background: IgAN, characterized by renal deposition of IgA, involves a multi-hit development with formation of circulating immune complexes (CICs) containing Gd-IgA1 and sCD89, contributing to renal inflammation. A Proliferation-Inducing Ligand (APRIL) is implicated in the immune response. The aim of this study is to investigate APRIL implication, especially in children with IgAN (cIgAN), who often exhibit more inflammation than adults. Methods: First, we evaluated APRIL levels in human mesangial cells (HMC) after stimulation with recombinant sCD89 (rsCD89) or plasma from cIgAN patients. Subsequently, we conducted a comprehensive international cross-sectional study involving 86 cIgAN patients and 48 control recruited from France and Canada. Our investigation included quantification of APRIL plasma levels and CICs, which were then compared with biological, clinical, and histological characteristics of the disease. Additionally, we performed immunohistochemistry analysis on kidney biopsies from cIgAN patients to visualize APRIL staining patterns. Results: We demonstrated first that stimulations with cIgAN plasma and rsCD89 induced inflammation in HMC, leading to increased APRIL mRNA and protein production. We observed elevated levels of Gd-IgA1, sCD89-IgA1, sCD89 and soluble APRIL in the plasma of cIgAN patients compared to control subjects. Moreover, we found evidence suggesting that APRIL may be trapped within CICs, colocalizing with IgA in same-size complexes in Western blot experiments.Plus, IgA-APRIL and CD89-APRIL complexes were detected in cIgAN samples using ELISA and immunoprecipitation techniques. Levels of CICs correlated with plasma APRIL levels, and presence of IgA-APRIL and CD89-APRIL in CICs was linked to a worst initial clinical presentation, prognosis with kidney failure and relapses with persistent proteinuria. Staining of cIgAN biopsies revealed the presence of APRIL deposits within the glomerulus in the mesangium and near the Bowman capsule. Conclusion: Our research highlights the role of APRIL in the pathways of cIgAN, with sCD89 as a potential trigger of APRIL activation in HMCs. APRIL holds promise as a valuable biomarker, offering a non-invasive means to detect forms of cIgAN with the worst progression, thereby potentially reducing reliance on biopsy. APRIL inhibition as therapeutic strategy presents an exciting opportunity for cIgAN treatment.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".